1354 PART 5 Infectious Diseases

forms of anaerobic cellulitis that may involve some gas formation but

often present without fever or extensive local pain and can spread over

the course of days rather than minutes.

Progressive bacterial synergistic gangrene (Meleney gangrene) is

characterized by an area of exquisite pain, redness, and swelling

followed by ulceration. As the ulcer enlarges, it is surrounded by a

violaceous ring that fades into a pink edematous border. If it is not

promptly treated, the ulcer continues to enlarge, and new, distant ulcers

may emerge. Symptoms are limited to pain; fever is not typical. Peptostreptococci and microaerophilic streptococci are commonly found in

the leading edge of the lesions, and S. aureus and Proteus species can be

isolated from the ulcerated lesion. Treatment includes surgical removal

of necrotic tissue and antimicrobial administration. In contrast, synergistic necrotizing cellulitis involves the deep fascia and occurs near

the point of bacterial entry. Pain, fever, and systemic symptoms are

common. If this form of cellulitis involves the scrotum, perineum, and

anterior abdominal wall, it is referred to as Fournier gangrene. S. aureus,

the B. fragilis group, Peptostreptococcus species, Clostridium species,

Fusobacterium species, and members of the family Enterobacteriaceae

are the predominant organisms identified.

Necrotizing fasciitis, a rapidly spreading destructive disease of the

fascia, is usually attributed to group A streptococci (Chap. 148) but

can also be a mixed infection involving anaerobes and aerobes. Polymicrobial necrotizing fasciitis differs from stereotypical group A streptococcal necrotizing fasciitis in that the initial erythematous, swollen,

tender lesions progress over 3–5 days (as opposed to 1–3 days), with

consequent skin breakdown and cutaneous gangrene. Fever, subcutaneous gas, development of anesthesia (often before skin necrosis), and

a foul-smelling discharge are common. The particular clinical findings

sometimes suggest the causative agent: regional lymphadenopathy

suggests the B. fragilis group; necrosis and gangrene suggest Clostridium species, peptostreptococci, the B. fragilis group, and Enterobacteriaceae; bullous lesions suggest Enterobacteriaceae; a foul-smelling

odor suggests Bacteroides and Clostridium species; and subcutaneous

gas suggests peptostreptococci, Clostridium species, and the B. fragilis

group. Moreover, diabetic infections are often associated with Bacteroides species, Enterobacteriaceae, and S. aureus, and infections related to

trauma are associated with Clostridium species.

Although S. aureus is the typical cause of myositis, anaerobes—

particularly C. perfringens—are often recovered from patients with

pyogenic myositis. In anaerobic streptococcal myonecrosis, peptostreptococci are often identified along with group A streptococci or S.

aureus. Patients typically present with fever, muscle pain, fatigue, and

an elevated creatinine kinase level suggestive of muscle inflammation.

Bone and Joint Infections A comprehensive review of the world

literature on anaerobic bone infections included >650 cases. Of these,

~400 cases were caused by Actinomyces species; anaerobic cocci and

Bacteroides, Fusobacterium, and Clostridium species were most commonly identified in the remaining cases. Actinomycotic involvement

of the jaw was the most common bone infection, with the mandible

involved four times as frequently as the maxilla. Patients with cervicofacial actinomycosis (Chap. 175) are often described as having a

“lumpy jaw” because of the prominent soft tissue swelling that is sometimes mistaken for malignancy or granulomatous disease. These infections can be chronic in nature, can include the development of sinus

tracts, can progress across normal tissue boundaries, and can require

prolonged antibiotic treatment to prevent relapse. The vertebrae are the

second most common location for Actinomyces infection; involvement

of the thorax, abdomen, or pelvis is much less frequent.

Osteomyelitis involving anaerobes other than Actinomyces species most

commonly develops by extension of an adjacent infection (e.g., soft tissue,

paranasal sinus, or middle-ear infection). For example, diabetic foot

ulcers and decubitus ulcers may be complicated by mixed aerobic–anaerobic osteomyelitis (Chap. 131). Hematogenous seeding of bone by anaerobes is uncommon and is thought to occur in fewer than 10% of cases.

The most common sites of anaerobic osteomyelitis are the head (skull and

jaw) and the extremities. Fusobacteria have been isolated in pure culture

from infections of the mastoid, mandible, and maxilla. Clostridium species

have been reported as anaerobic pathogens in cases of osteomyelitis of the

long bones following trauma. Anaerobic and microaerophilic cocci are

most frequently isolated from infections involving the skull or mastoid;

usually, these organisms are present in mixed cultures.

In contrast to anaerobic osteomyelitis, anaerobic arthritis (Chap.

130) is uncommon, typically involving a single isolate, and most cases

are secondary to hematogenous spread. Although Fusobacterium species accounted for nearly one-third of cases in the preantibiotic era,

C. acnes, peptostreptococci, and B. fragilis are now among the more

frequent causes of anaerobic septic arthritis. Peptostreptococci and C.

acnes are often found in association with prosthetic joints, Fusobacterium species have a predilection for the sternoclavicular and sacroiliac

joints, and clostridial arthritis is especially common after trauma. As a

frequent cause of bacteremia, B. fragilis is a common cause of anaerobic

septic arthritis; however, arthritis occurs in fewer than 5% of patients

with B. fragilis bacteremia.

Bacteremia B. fragilis is the anaerobe most commonly isolated from

blood cultures. Although the frequency of positive cultures appeared to

be decreasing in the 1980s, more recent evidence suggests that the rate

is now increasing and that the increase may be related to changing

demographics, with more patients who are elderly, immunocompromised, and/or receiving medications that may disrupt the mucosal

barrier (e.g., chemotherapy). The source of bacteremia is most often an

abscess in the abdomen, female genital tract, or soft tissue. At a large

tertiary-care U.S. hospital, 0.8% of all positive blood cultures yielded

an anaerobic gram-negative bacillus, with 0.5% yielding B. fragilis. A

similar study in France revealed that 0.6% of all positive blood cultures

yielded an anaerobic organism; 60% of these isolates were Bacteroides

species, and 22% were Clostridium species. Peptostreptococcus and

Fusobacterium species are also recovered with significant frequency.

Once the organism in the blood has been identified, both the portal

of bloodstream entry and the underlying problem that probably led to

seeding of the bloodstream can often be deduced from an understanding of the organism’s normal site of residence. For example, mixed

anaerobic bacteremia including B. fragilis usually implies a colonic

pathology, with mucosal disruption from neoplasia, diverticulitis,

or some other inflammatory lesion. The initial manifestations are

determined by the portal of entry and reflect the localized condition.

Although the clinical manifestations of B. fragilis bacteremia (e.g.,

rigors, hectic fevers) are similar to those of aerobic gram-negative bacillary bacteremia, the incidence of septic shock is lower with B. fragilis.

This difference may be due to differences in the immunostimulatory

effects of the different endotoxin structures.

In virtually all cases, isolation of a member of the B. fragilis group

from blood indicates underlying infection that is associated with a mortality rate of 60% if untreated. It has been suggested that the mortality

rate depends in part on the species recovered (B. thetaiotaomicron >

P. distasonis > B. fragilis), but it is unclear whether differences in mortality rates relate to intrinsic differences in the virulence of these organisms,

in their antimicrobial susceptibility profiles, and/or in the host’s immune

response. Case–fatality rates appear to increase with the increasing age

of the patient (with reported rates of >66% among patients >60 years

old), with the isolation of multiple species from the bloodstream, and

with the failure to surgically remove a focus of infection.

Endocarditis (See also Chap. 128) Although gram-negative anaerobic bacteria only rarely cause endocarditis, their involvement is associated with significant mortality rates (21–43%). Members of the B.

fragilis group are the most commonly identified gram-negative anaerobes in endocarditis. Anaerobic streptococci, which are often classified

incorrectly, are likely responsible for this disease more frequently than

is generally appreciated. Compared to aerobic bacterial endocarditis,

endocarditis due to Bacteroides species is less likely to be associated

with a history of cardiovascular disease and more likely to involve

thromboembolic complications.

■ DIAGNOSIS

There are three critical steps in the diagnosis of anaerobic infection: (1)

proper collection of specimens; (2) rapid transport of the specimens to

1355CHAPTER 177 Infections Due to Mixed Anaerobic Organisms

the microbiology laboratory, preferably in anaerobic transport media;

and (3) proper handling of the specimens by the laboratory. Specimens must be collected by meticulous sampling of infected sites, with

avoidance of contamination by the normal microbiota. Samples from

sites known to harbor numerous anaerobes (e.g., the mouth, nose,

vagina, feces) are not acceptable for anaerobic culture as the presence

of the normal microbiota will complicate interpretation of the results

in a clinically meaningful manner. In contrast, samples from normally

sterile locations (e.g., blood, pleural fluid, peritoneal fluid, CSF, and

aspirates or biopsy samples from normally sterile sites) are appropriate

for anaerobic culture in clinical microbiology laboratories. As a general

rule, liquid or tissue specimens are preferred; if swab specimens must

be used, special anaerobic swab systems should be used to help maintain persistence of anaerobes. Liquid samples should be collected in an

air-free syringe that is then capped, injected into anaerobic transport

bottles, or quickly transported to the clinical microbiology laboratory

for immediate culture.

Because of the time and difficulty involved in the isolation of anaerobic bacteria, the diagnosis of anaerobic infections must frequently be

based on presumptive evidence. As mentioned previously, anaerobic

infections are sometimes suggested by specific clinical factors, such as

origins from a site with an anaerobic-rich microbiota (e.g., the intestinal tract, oropharynx), the presence of an abscess, involvement of sites

with lowered oxidation-reduction potential (e.g., avascular necrotic

tissues), a foul odor, and the presence of gas in tissues. None of these

features is necessarily pathognomonic or required for the diagnosis

of an anaerobic infection, but these are helpful clues to keep in mind

when constructing a differential diagnosis.

When cultures of obviously infected sites or purulent material yield no

growth, streptococci only, or a single aerobic species (such as E. coli) and

Gram’s staining reveals a mixed bacterial population, the involvement

of anaerobes should be suspected; the implication is that the anaerobic

microorganisms have failed to grow because of inadequate transport

and/or culture techniques. It is also important to remember that prior

antibiotic therapy reduces the cultivability of these bacteria. Failure of an

infection to respond to antibiotics that are not active against anaerobes

(e.g., aminoglycosides and—in some circumstances—penicillin, cephalosporins, or tetracyclines) suggests an anaerobic etiology.

TREATMENT

Anaerobic Infections

Similar to successful therapy for other types of infection, treatment

for anaerobic infections requires the administration of appropriate antibiotics, surgical debridement of devitalized tissues, and

drainage of any large abscess. Any mucosal breach must be closed

promptly to prevent ongoing infection.

ANTIBIOTIC THERAPY AND RESISTANCE

The antibiotics used to treat anaerobic infections should be active

against both aerobic and anaerobic organisms because many of

these infections are of mixed etiology. Antibiotic regimens can

usually be selected empirically on the basis of the location of infection (which provides insight into the likely species involved), the

severity of infection, and knowledge of local antimicrobial resistance patterns. Other factors influencing the selection of antibiotics

include need for penetration into certain organs (such as the brain)

and associated toxicity (Chap. 144). As with all infections, the

general maxim is to use the least broad-spectrum agent(s) possible

so as to minimize the impact on the normal microbiota and the

development of resistance.

Because of the slow growth rate of many anaerobes, the lack of

standardized testing methods and of clinically relevant standards for

resistance, and the generally good results obtained with empirical

therapy, the role of antibiotic susceptibility testing of these organisms has been limited in most clinical microbiology laboratories.

Instead, isolates are sent to reference laboratories for susceptibility

testing when an infection is serious (e.g., brain abscess, meningitis,

joint infection), is refractory, or requires prolonged therapy (e.g.,

osteomyelitis, prosthetic joint infection, endocarditis). Such testing

should also be considered when a patient is not responding to antimicrobial therapy as expected; multidrug-resistant anaerobes have

been reported. Antimicrobial susceptibility testing is also helpful in

monitoring the activity of new drugs and recording current resistance patterns among anaerobic pathogens.

The need for susceptibility testing of anaerobic organisms is highlighted by increasing rates of antimicrobial resistance, geographic

and institutional differences in susceptibility profiles, speciesspecific antibiograms, and the potential for worse clinical outcomes

when ineffective antibiotics are used. These differences preclude

making any sweeping generalizations regarding antibiotic therapy for

anaerobic infections. For example, rates of resistance to piperacillintazobactam have remained low (≤1%) for all Bacteroides species in

the United States, but B. thetaiotaomicron isolates in Korea have a

notably higher resistance rate (17%). Clindamycin was historically

effective against members of the B. fragilis group, but rates of resistance have increased to 30–43% in the United States and are >80%

in some parts of the world. Furthermore, metronidazole is effective

against many different anaerobic organisms and is considered a

first-line agent for many anaerobic infections worldwide, but, in

a population of Colombian patients with refractory periodontitis,

45% of Fusobacterium isolates and 25% of Prevotella and Porphyromonas strains were resistant to metronidazole; this finding underscores the importance of understanding the local antibiogram and

of assessing susceptibility profiles in refractory disease.

Empirical Therapy Not every anaerobe isolated must be specifically targeted by the antibiotic regimen. Given that infections involving anaerobes are typically polymicrobial, that the cultivation and

identification of anaerobes are challenging (i.e., not all organisms

may be recovered), and that organisms often depend on one another

for persistence, clinical resolution of the infection is often achieved

with empirical antibiotics targeting the bulk of the organisms

recovered. Antibiotics that demonstrate no useful activity against

anaerobes include aminoglycosides, monobactams, and trimethoprim-sulfamethoxazole. With the caveat that susceptibility profiles

may change with time and geography, the antibiotics that are commonly used as empirical therapy against anaerobic bacteria include

metronidazole, β-lactam/β-lactamase inhibitor combinations, clindamycin, carbapenems, and chloramphenicol (Table 177-2).

Metronidazole is active against gram-negative anaerobes, including nearly all isolates of Bacteroides species, and gram-positive

spore-forming organisms, such as C. difficile (Chap. 134) and

other Clostridium species. Given intrinsically reduced susceptibility,

metronidazole is clinically unreliable against gram-positive nonspore-forming organisms, such as Actinomyces, Propionibacterium,

Lactobacillus, Bifidobacterium, Eubacterium, and Peptostreptococcus.

TABLE 177-2 Antimicrobial Therapy That Is Typically Active Against

Commonly Encountered Anaerobes

ANTIBIOTIC(S) CAVEATS

Metronidazole This drug is clinically unreliable against grampositive non-spore-forming anaerobes (e.g.,

Actinomyces spp., Propionibacterium spp.,

Peptostreptococcus spp.).

β-Lactam/β-lactamase

inhibitor combinations

(ampicillin-sulbactam,

ticarcillin–clavulanic acid,

piperacillin-tazobactam)

Rates of resistance are increasing in some gramnegative anaerobes. The newer cephalosporin/

β-lactamase combinations have limited

anaerobic activity.

Clindamycin Rates of resistance are increasing in Bacteroides

spp.

Carbapenems (meropenem,

imipenem, ertapenem,

doripenem)

Rates of resistance are currently very low (<5%),

although some carbapenemase-producing strains

have been identified.

Chloramphenicol Some clinical failures have been noted, even

when the isolate is found to be susceptible by in

vitro testing.

1356 PART 5 Infectious Diseases

Of note, a few metronidazole-resistant Bacteroides isolates have

been identified in the United States, and rates of such resistance

have been increasing in Europe. Moreover, the rate of resistance

to metronidazole has probably been greatly underestimated in

some countries (e.g., the United Kingdom) that use metronidazole

susceptibility to discriminate between obligate and facultative

anaerobes (with obligate anaerobes defined by their susceptibility).

Although the majority of metronidazole-resistant isolates have been

identified in patients who have been exposed to the drug, resistant

organisms have also been found in metronidazole-naïve patients.

More than 90% of clinical isolates from the B. fragilis group produce β-lactamases that are predominantly active against cephalosporins and that are highly active, cell associated, and produced

constitutively. Thus, members of the B. fragilis group are presumed

to be resistant to penicillin and ampicillin but may remain susceptible to extended-spectrum penicillins, particularly in combination

with a β-lactamase inhibitor (e.g., ampicillin-sulbactam, piperacillintazobactam). Rates of resistance to ampicillin-sulbactam are increasing,

particularly in P. distasonis, which has a reported resistance rate of 21%

in the United States. Because β-lactamase production is not common in

Clostridium species, these combination agents are usually effective. Of

note, the newer cephalosporin/β-lactamase inhibitors (e.g., ceftolozanetazobactam, ceftazidime-avibactam) have limited anaerobic activity.

Clindamycin is active against many anaerobes. However, rates of

resistance to clindamycin among Bacteroides species increased in

the United States from 7% in 1981 to 33% in 2010–2012. Resistance

to clindamycin among non-Bacteroides gram-negative anaerobes is

much less common (<10%). Some Clostridium species are resistant

to clindamycin, although C. perfringens typically is not.

Carbapenems (ertapenem, doripenem, meropenem, and imipenem) are active against anaerobes, with fewer than 3% of Bacteroides isolates resistant. There is little difference among resistance rates

for specific species, and, of the carbapenems, imipenem typically

has the lowest resistance rate. Although the β-lactamase produced

by most Bacteroides species is unable to inactivate carbapenems, rare

B. fragilis strains have been reported to produce a carbapenemase.

Resistance to chloramphenicol is rare in Bacteroides species.

Nationwide surveys in the United States have identified no resistant

organisms, but some isolates with elevated minimal inhibitory concentrations (MICs)—i.e., 16 μg/mL—have been noted. Although chloramphenicol has excellent in vitro activity against all clinically relevant

anaerobes, some clinical failures have been documented. Therefore,

this drug may be less preferable if other active agents are available.

Other antibiotics with more variable activity against anaerobes include the fluoroquinolones and tigecycline. Although many

fluoroquinolones (e.g., ciprofloxacin, levofloxacin, ofloxacin) display reasonable activity against anaerobic organisms other than

Bacteroides species, these agents exhibit poor activity against the

B. fragilis group. Rates of resistance to moxifloxacin are relatively

high (39–83%) among Bacteroides isolates obtained in the United

States but are much lower among B. fragilis and B. thetaiotaomicron

isolates collected in Korea (8 and 2%, respectively) or Taiwan (8 and

15%, respectively). Tigecycline is active against most anaerobic bacteria, although MICs are somewhat higher for Clostridium species.

Tigecycline’s efficacy for treatment of complicated intraabdominal

infections is comparable to that of imipenem, and it is therefore

recommended as single-agent therapy for these infections.

Infections at Specific Sites In clinical situations, specific antibiotic regimens and durations must be tailored to the initial site of

infection; the reader is referred to specific chapters on infections at

specific sites for recommendations. In general, anaerobic infections

are often broadly categorized as originating above or below the diaphragm. This distinction is clinically useful in that the predominant

pathogens—and therefore the empirical antibiotic regimens—differ

between these two categories of infection.

Infections above the diaphragm usually reflect the orodental

microbiota, which includes Prevotella, Porphyromonas, Fusobacterium, and Bacteroides species other than the B. fragilis group along

with streptococci (both aerobic and microaerophilic). Accordingly,

antibiotic regimens should cover both aerobic and anaerobic bacteria. Given that >70% of these infections include a β-lactamaseproducing organism, β-lactam drugs (penicillins and cephalosporins) are poor options as monotherapy. The recommended regimens

include clindamycin, a β-lactam/β-lactamase inhibitor combination, or metronidazole in combination with a drug active against

microaerophilic and aerobic streptococci (e.g., penicillin).

Anaerobic infections arising below the diaphragm (e.g., colonic

and intraabdominal infections) must be treated specifically with

agents active against Bacteroides species, including B. fragilis. Single

agents suitable for this purpose include cefoxitin, moxifloxacin, a

β-lactam/β-lactamase inhibitor combination, or a carbapenem. A

two-drug regimen is an alternative, with one drug active against

anaerobes and the other against coliforms (e.g., metronidazole with

either a cephalosporin or a fluoroquinolone). In addition, if the

clinician suspects that gram-positive facultative organisms such

as enterococci are involved, therapeutic regimens should include

ampicillin or vancomycin. Although clindamycin and cefotetan

were previously considered acceptable options for intraabdominal

infections involving anaerobes, these drugs are no longer recommended because of escalating rates of resistance in the B. fragilis

group. Ampicillin-sulbactam is not recommended because of high

rates of resistance among community-acquired strains of E. coli

rather than because of resistance in anaerobic bacteria.

CNS infections involving anaerobic organisms may be treated

with metronidazole, a carbapenem, chloramphenicol, or—if only

gram-positive anaerobes are involved—penicillin. Clindamycin and

cefoxitin have poor penetration into the CSF and should not be used.

Cases of osteomyelitis in which a polymicrobial infection is identified

from a bone biopsy specimen should be treated with a regimen that

covers both aerobes and anaerobes, as some organisms that are often

regarded as a contaminant (e.g., C. acnes) may have a pathogenic role.

When an anaerobic organism is recognized as a major or sole pathogen infecting a joint, the duration of treatment should be similar to

that used for arthritis caused by aerobic bacteria (Chap. 130).

Although not every anaerobe needs to be covered with pathogendirected therapy in most polymicrobial infections, several studies of

Bacteroides bacteremia have clearly demonstrated that patients receiving effective therapy have lower mortality rates and more rapid sterilization of blood cultures than patients receiving ineffective therapy.

FAILURE OF THERAPY

Anaerobic infections that fail to respond to treatment or that relapse

should be reassessed. Potential causes include an uncontrolled

source of infection (e.g., ongoing intestinal leak into the peritoneum), superinfection with a new organism, and/or antibiotic failure. Additional imaging may be useful to discern whether surgical

drainage or debridement is warranted. Obtaining additional culture

specimens will help identify whether an organism resistant to the

antibiotics being used is present. Strong consideration should be

given to obtaining susceptibility profiles for the isolates.

■ FURTHER READING

Brook I: Antimicrobial therapy of anaerobic infections. J Chemother

28:143, 2016.

Cooley L, Teng J: Anaerobic resistance: Should we be worried? Curr

Opin Infect Dis 32:523, 2019.

Finegold SM: Anaerobes: Problems and controversies in bacteriology,

infections, and susceptibility testing. Rev Infect Dis 12(Suppl 2):S223,

1990.

Kierzkowska M et al: Trends and impact in antimicrobial resistance

among Bacteroides and Parabacteroides species in 2007-2012 compared to 2013-2017. Microb Drug Resist 26:1452, 2020.

Styrt B, Gorbach SL: Recent developments in the understanding of

the pathogenesis and treatment of anaerobic infections (2). N Engl J

Med 321:240, 1989.

Wexler HM: Bacteroides: The good, the bad, and the nitty-gritty. Clin

Microbiol Rev 20:593, 2007.

1357CHAPTER 178 Tuberculosis

Section 8 Mycobacterial Diseases

178

Tuberculosis (TB), which is caused by bacteria of the Mycobacterium

tuberculosis complex, is one of the oldest diseases known to affect

humans and the top cause of infectious death worldwide excluding

COVID-19. Population genomic studies suggest that M. tuberculosis

may have emerged ~70,000 years ago in Africa and subsequently

disseminated along with anatomically modern humans, expanding

globally during the Neolithic Age as human density started to increase.

Progenitors of M. tuberculosis are likely to have affected prehominids.

This disease most often affects the lungs, although other organs are

involved in up to one-third of cases. If properly treated, TB caused

by drug-susceptible strains is curable in the vast majority of cases.

If untreated, the disease may be eventually fatal in over 70% of people. Transmission usually takes place through the airborne spread of

droplet nuclei produced by patients with infectious pulmonary TB.

Through pharmacological prophylaxis the development of the disease

can be prevented in those who have contracted TB infection.

ETIOLOGIC AGENT

Mycobacteria belong to the family Mycobacteriaceae and the order

Actinomycetales. Of the pathogenic species belonging to the M. tuberculosis complex, which comprises eight distinct subgroups, the most

common and important agent of human disease by far is M. tuberculosis

(sensu stricto). A closely related organism isolated from cases in West,

Central, and East Africa is M. africanum. The complex includes some

zoonotic members, such as M. bovis (the bovine tubercle bacillus—

characteristically resistant to pyrazinamide, once an important cause

of TB transmitted by unpasteurized milk, and currently responsible for

140,000 human cases worldwide in 2019, half of them in Africa) and

M. caprae (related to M. bovis). In addition, other organisms that have

been reported rarely as causing TB include M. pinnipedii (a bacillus

infecting seals and sea lions in the southern hemisphere and recently

isolated from humans), M. mungi (isolated from banded mongooses in

southern Africa), M. orygis (described in oryxes and other Bovidae in

Africa and Asia and a potential cause of infection in humans), and M.

microti (the “vole” bacillus, a less virulent organism). Finally, M. canetti

is a rare isolate from East African cases that produces unusual smooth

colonies on solid media and is considered closely related to a supposed

progenitor type. There is no known environmental reservoir for any of

these organisms.

M. tuberculosis is a rod-shaped, non-spore-forming, thin aerobic

bacterium measuring 0.5 μm by 3 μm. Mycobacteria, including M.

tuberculosis, are often neutral on Gram’s staining. However, once

stained, the bacilli cannot be decolorized by acid alcohol; this characteristic justifies their classification as acid-fast bacilli (AFB; Fig. 178-1).

Acid fastness is due mainly to the organisms’ high content of mycolic

acids, long-chain cross-linked fatty acids, and other cell-wall lipids.

Microorganisms other than mycobacteria that display some acid fastness include species of Nocardia and Rhodococcus, Legionella micdadei,

and the protozoa Isospora and Cryptosporidium. In the mycobacterial

cell wall, lipids (e.g., mycolic acids) are linked to underlying arabinogalactan and peptidoglycan. This structure results in very low permeability of the cell wall, thus reducing the effectiveness of most antibiotics.

Another molecule in the mycobacterial cell wall, lipoarabinomannan,

is involved in the pathogen–host interaction and facilitates the survival

of M. tuberculosis within macrophages.

The complete genome sequence of M. tuberculosis comprises 4.4

million base pairs, 4043 genes encoding 3993 proteins, and 50

genes encoding stable RNAs; its high guanine-plus-cytosine

content (65.6%) is indicative of an aerobic “lifestyle.” A large proportion

of genes are devoted to the production of enzymes involved in cell wall

metabolism. Substantial genetic variability exists among the innumerable M. tuberculosis strains from different parts of the world. Based on

such genetic variability it is possible to distinguish and compare different strains. Their distinction is important to study transmission dynamics and identify outbreaks. Starting in the 1990s, reproducible

genotyping methods were developed to type the bacterium. Initially,

they included insertion sequence 6110 (IS6110), restriction fragment

length polymorphism (RFLP) typing, and spoligotyping. Lately, most

studies utilize mycobacterial interspersed repetitive unit variable number tandem repeats (MIRU-VTNRs) and whole genome sequencing

analysis.

EPIDEMIOLOGY

In 2019, 7.1 million new cases of TB (all forms, both pulmonary and

extrapulmonary) were reported to the World Health Organization

(WHO) by its member states; 97% of cases were reported from lowand middle-income countries. However, because of insufficient case

detection and incomplete notification, reported cases represent only

about two-thirds of the total estimated cases. The WHO estimated that

10 million (range 9-11 million; rate 130 per 100,000 people) new (incident) cases of TB occurred worldwide in 2019, 97% of them in low- and

middle-income countries of Asia (6.1 million), Africa (2.4 million),

the Middle East (0.8 million), and Latin America (0.28 million). Eight

countries accounted for two-thirds of all new cases: India, Indonesia,

China, the Philippines, Pakistan, Nigeria, Bangladesh, and South

Africa. Of all cases, 57% occurred in male patients, 32% in female

patients, and 11% in children. It is further estimated that 1.4 million

(range, 1.3–1.6 million) deaths from TB, including 0.21 million among

people with HIV co-infection, occurred in 2019; 98% of these deaths

were in low- and middle-income countries. Estimates of TB incidence

rates (per 100,000 population) and numbers of TB-related deaths in

2018 are depicted in Figs. 178-2 and 178-3, respectively. During the

Tuberculosis

Mario C. Raviglione, Andrea Gori

FIGURE 178-1 Acid-fast bacillus smear showing M. tuberculosis bacilli. (Courtesy

of the Centers for Disease Control and Prevention, Atlanta.)

1358 PART 5 Infectious Diseases

late 1980s and early 1990s, numbers of reported cases of TB increased

in high-income countries after years of decline. These increases were

related largely to immigration from countries with a high incidence

of TB; the worldwide spread of the HIV epidemic; social problems,

such as increase in urbanization and the related increased urban poverty, homelessness, and drug abuse; and dismantling of TB services.

During the past few years, numbers of reported cases have begun to

decline again or have stabilized in most industrialized nations. In the

United States, with the re-establishment of stronger control programs,

the decline resumed in 1993, and during the period 2007−2012, the

decline rate was 6.5% annually on average. Later, between 2012 and

2019 this annual rate slowed down to 2.1%. In 2019, 8920 cases of TB

Incidence per 100,000

population per year

0–9.9

10–99

100–199

200–299

300–499

≥500

No data

Not applicable

FIGURE 178-2 Estimated tuberculosis (TB) incidence rates (per 100,000 population) in 2018. The designations used and the presentation of material on this map do not

imply the expression of any opinion whatsoever on the part of the World Health Organization (WHO) concerning the legal status of any country, territory, city, or area or of

its authorities or concerning the delimitation of its frontiers or boundaries. Dotted, dashed, and white lines represent approximate border lines for which there may not yet

be full agreement. (Reproduced with permission from Global Tuberculosis Report 2019. Geneva, World Health Organization; 2019.)

Mortality per 100,000

population per year

0–0.9

1–4.9

5–19

20–39

≥40

No data

Not applicable

FIGURE 178-3 Estimated tuberculosis (TB) mortality rates in HIV-negative people in 2018. (See disclaimer in Fig. 178-2. Reproduced with permission from Global Tuberculosis

Report 2019. Geneva, World Health Organization; 2019.)

1359CHAPTER 178 Tuberculosis

(2.7 cases/100,000 population) were preliminarily reported to the U.S.

Centers for Disease Control and Prevention (CDC).

In the United States, TB is uncommon among young white adults of

European descent, who have only rarely been exposed to M. tuberculosis

infection during recent decades. In contrast, because of a high risk of

transmission in the past, the prevalence of M. tuberculosis infection is

relatively high among elderly whites. In general, adults ≥65 years of age

have the highest incidence rate per capita and children <14 years of age

the lowest. Among U.S.-born persons, African Americans accounted

for the highest proportion of cases (35%; 905 in 2019), followed by

white persons (756 cases), and Hispanic/Latinos (628). TB in the

United States is also a disease of adult members of the HIV-infected

population (4.9% of all cases), the foreign-born population (71% of

all cases in 2019), and disadvantaged/marginalized populations. Of

the 6322 cases reported among non-U.S.-born persons in the United

States in 2019, 33% occurred in Hispanic/Latinos and 47% in persons

born in Asia. Overall, the highest rates per capita were among nonU.S.-born Asians (26 cases/100,000 population) and native Hawaiian/

Pacific Islanders (25 cases/100,000 population). A total of 515 deaths

was caused by TB in the United States in 2017. In Canada, TB cases and

rates per 100,000 population have been increasing between 2014 and

2017 (from 1615/4.5 to 1796/4.9). In 2017, 1796 TB cases were reported

(4.9 cases/100,000 population); 72% (1290) of these cases occurred in

foreign-born persons, and 17.4% (313 cases) occurred in Canadian-born

Indigenous Peoples, whose per capita rate is disproportionately high

(21.5 cases/100,000 population). The highest rate was found in the

territory of Nunavut, at 265 cases/100,000 population—a rate similar

to that in many highly endemic countries. Similarly, in Europe, TB

has reemerged as an important public health problem, mainly as a

result of cases among immigrants from high-incidence countries and

among marginalized populations, often in large urban settings such as

London. In 2018, 36% of all cases reported from England occurred in

London, 82% of them among people born abroad; although decreasing,

the rate per capita (19 cases/100,000 population) is twice as high as that

of England with a borough (Newham) reaching 47 cases per 100,000

population. Likewise, in most Western European countries, there are

more cases annually among foreign-born than native populations.

Recent data on global trends indicate that in 2019 the TB incidence

was stable or falling in most regions; this trend began in the early 2000s

and appears to have continued, with an average annual decline of 1.7%

globally and 2.3% between 2018 and 2019. This global decrease is

explained largely by the reduction in TB incidence in sub-Saharan Africa,

where rates had risen steeply since the 1980s as a result of the HIV epidemic and the lack of capacity of health systems and services to deal with

the problem effectively, and, less so, in Eastern Europe, where incidence

increased rapidly during the 1990s because of a deterioration in socioeconomic conditions and the health care infrastructure (although, after

peaking in 2001, incidence in Eastern Europe has since declined slowly).

Of the estimated 10 million new cases of TB in 2019, 8.2%

(0.82 million) were associated with HIV co-infection, and 73% of these

HIV-associated cases occurred in Africa. An estimated 0.21  million

persons with HIV-associated TB died in 2019. Furthermore, an

estimated 465,000 (range 400,000-535,000) cases of rifampin- (also

called rifampicin) resistant TB (RR-TB) and multidrug-resistant TB

(MDR-TB)—a form of the disease caused by bacilli resistant at least

to isoniazid and rifampin—occurred in 2019, representing 3.3% and

18%, respectively, of all new and previously treated cases. Only 44%

of these cases were diagnosed because of a lack of culture and drug

susceptibility testing (DST) capacity in many settings worldwide. As a

consequence, an estimated 200,000 people with MDR/RR-TB died in

2019. The countries of the former Soviet Union reported the highest

proportions of MDR/RR disease among new TB cases (37% in Belarus,

35% in Russia, 29% in Kyrgyzstan, Moldova, and Ukraine). Overall,

half of all MDR/RR-TB cases occur in India (27%), China (14%), and

the Russian Federation (9%). Since 2006, 131 countries, including the

United States, have reported cases of extensively drug-resistant TB

(XDR-TB), in which MDR-TB is compounded by additional resistance to any fluoroquinolones and at least one of the injectable drugs

amikacin, kanamycin, and capreomycin. (N.B: In January 2021, the

WHO published the following new definitions: (i) Pre-XDR-TB, as TB

caused by Mycobacterium tuberculosis strains that fulfill the definition

of MDR/RR-TB and that are also resistant to any fluoroquinolone.

(ii) XDR-TB, as TB caused by Mycobacterium tuberculosis strains

that fulfill the definition of MDR/RR-TB and that are also resistant

to any fluoroquinolone and at least one additional Group A drug

including levofloxacin or moxifloxacin, bedaquiline and linezolid.)

About 6.2% of the MDR-TB cases worldwide may be XDR-TB, but the

vast majority of XDR-TB cases remain undiagnosed because reliable

methods for DST are lacking and laboratory capacity is limited mainly

in low-income countries. Lately, a few cases deemed resistant to all

anti-TB drugs have been reported; however, this information must be

interpreted with caution because susceptibility testing for several second-line drugs is neither accurate nor reproducible.

■ FROM EXPOSURE TO INFECTION

M. tuberculosis is most commonly transmitted from a person with

infectious pulmonary TB by droplet nuclei containing M. tuberculosis

bacteria, which are aerosolized by coughing, sneezing, or speaking.

The tiny droplets dry rapidly; the smallest (<5–10 μm in diameter)

may remain suspended in the air for several hours and may reach the

terminal air passages when inhaled. There may be as many as 3000

infectious nuclei per cough. Other routes of transmission of tubercle

bacilli (e.g., through the skin or the placenta) are uncommon and of

no epidemiologic significance. The risk of transmission and of subsequent acquisition of M. tuberculosis infection is determined mainly

by exogenous factors, although endogenous factors may also play a

role. The probability of contact with a person who has an infectious

form of TB, the intimacy and duration of that contact, the degree of

infectiousness of the case, and the shared environment in which the

contact takes place are all important determinants of the likelihood of

transmission. Several studies of close-contact situations have clearly

demonstrated that TB patients whose sputum contains AFB visible

by microscopy (sputum smear–positive cases) are the most likely to

transmit the infection. The most infectious patients have cavitary

pulmonary disease or, much less commonly, laryngeal TB and produce

sputum containing as many as 105

–107

 AFB/mL. Patients with sputum

smear–negative/culture-positive TB are less infectious, although they

have been responsible for up to 20% of transmission in some studies

in the United States. Those with culture-negative pulmonary TB and

extrapulmonary TB are essentially noninfectious. Because persons

with both HIV infection and TB are less likely to have cavitations, they

may be less infectious than persons without HIV co-infection. Crowding in poorly ventilated rooms is one of the most important factors in

the transmission of tubercle bacilli because it increases the intensity of

contact with a case. The virulence of the transmitted organism is also

an important factor in establishing infection. Endogenous factors such

as the degree of immune competence are also important. In particular,

HIV-infected patients, persons undergoing cancer treatment, or those

administered immunosuppressive drugs may be at higher risk of TB

infection acquisition.

Because of delays in seeking care and in making a diagnosis, it has

been estimated that, in high-prevalence settings, up to 20 contacts

(or 3–10 people per year) may be infected by each AFB-positive case

before the index case is diagnosed. Attempts to estimate the basic

reproductive number R0

 for TB have resulted in a wide range of values

depending on environmental conditions and social behaviors of populations: from 0.24 in the Netherlands during the period 1933−2007 to

4.3 in China in 2012 reflecting the status of disease control.

■ FROM INFECTION TO DISEASE

Unlike the risk of acquiring infection with M. tuberculosis, the risk of

developing disease after being infected depends largely on endogenous

factors, such as the individual’s innate immunologic and nonimmunologic defenses and the level at which the individual’s cell-mediated

immunity is functioning. Clinical illness directly following infection is

classified as primary TB and is common among children in the first few

years of life and among immunocompromised persons. Although primary TB may be severe and disseminated, it generally is not associated